Decreased Histamine Catabolism in the Colonic Mucosa of Patients with Colonic Adenoma

Introduction Alterations in mucosal histamine degradation play an important role in various gastrotinestinal diseases including colonic adenoma. In humans, histamine can be catabolized either by oxidative deamination by diamine oxidase (DAO) or by ring methylation by histamine N-methyltransferase (HNMT). The significance of HNMT in this context was investigated for the first time in this project. Methods About 94 colonic biopsies were endoscopically obtained from 23 patients suffering from colonic adenoma and 26 biopsies from six healthy individuals. Each sample was mechanically homogenized, homogenates were cleared by centrifugation and used for determination of protein and histamine concentrations and enzyme activities of DAO and HNMT by radiometric assay. Results In adenoma patients DAO activities were slightly and HNMT activities were significantly decreased in normal mucosa compared to controls. Activities of both enzymes were significantly lower in adenoma tissue than in healthy mucosa in the same patients. A significant correlation was found between HNMT and DAO in all investigated samples. Histamine concentrations were elevated in adenoma patients. Conclusions Histamine catabolism is decreased in the colonic mucosa of patients with colonic adenoma.     

DNA甲基转移酶1和3A在结直肠癌组织中的表达及其与临床病理的关系

目的:探讨DNA甲基转移酶1(DNMT1)和DNA甲基转移酶3A(DNMT3A)在结直肠正常组织、腺瘤、腺癌中的表达,及其可能的临床病理意义.方法:以免疫组织化学SP法检测DNMT1和DNMT3A在正常结直肠组织、腺瘤、腺癌中的表达.通过计算染色指数(SI),评估两者的表达水平与年龄、肿瘤大小、分期、分化等临床病理特征之间的关系.采用Kaplan-Meier法进行生存分析.结果:DNMT3A在正常组织和腺瘤中表达明显低于癌组织(SI:10.5±5.7vs20.2±9.9,P<0.05).DNMT1在三者中的表达呈递增趋势,SI分别为10.3±2.7、14.7±6.8、20.1±9.1.淋巴结转移病例DNMT1表达高于未转移病例(18.1±7.9vs12.0±6.3,P<0.05),浸润深度超过肌层病例DNMT1和DNMT3A表达高于未超过肌层病例,差异均有统计学意义(20.1±10.1vs15.8±7.9;19.9±8.5vs15.4±4.7,均P<0.05).结论:DNMT1和DNMT3A是结直肠癌发生的早期事件,两者共同促进结直肠癌的发生发展,可能成为结直肠癌治疗的新靶点.     

Effect of Resistant Starch on Potential Biomarkers for Colonic Cancer Risk in Patients with Colonic Adenomas

Resistant starch decreases the concentration of secondary bile acids in the feces and the proliferation rate of colonic mucosal cells in healthy volunteers. This may reduce the risk of colon cancer. We investigated 23 patients with recently removed colonic adenoma(s) in a controlled parallel trial. They consumed 45 g of maltodextrin per day as placebo for four weeks and were randomly assigned to either 45 g of native amylomaize starch, containing 28 g of resistant starch type II or 45 g of maltodextrin for another four weeks. No effect on colorectal cell proliferation, fecal wet and dry weights, pH, and short-chain fatty acid excretion was seen. The bile acid concentration in fecal water decreased by 15% (P = 0.048) and the percentage secondary bile acids decreased by 14% (P = 0.002) on resistant starch relative to placebo. Whether this has a substantial role in colon cancer prevention in these patients remains to be established.     

A microspectrophotometric study of DNA ploidy patterns of colorectal adenomas

Eighty-four adenomas (31 mild, 25 moderate, 28 severe atypia), 32 invasive carcinomas and 15 samples of normal mucosa were collected form polypectomy and surgically resected specimens, and their DNA ploidy patterns were examined by microspectrophotometry. The frequency of polyploidy and aneuploidy were 7% and 0% in normal mucosa, 13% and 0% in mild atypia, 20% and 44% in moderate atypia, 32% and 22% in severe atypia and 31% and 53% in invasive carcinomas, respectively. Furthermore, these abnormal ploidy patterns were found frequently in moderate atypia accompanying severe atypia and mild atypia accompanying moderate atypia. These findings suggest that adenomas with moderate atypia might be the early stage of histologically overt cancer. The thin-section method (4 μm or 7μm) was useful for measuring regional DNA ploidy patterns of colorectal adenoma.     

Clinicopathological and molecular features of colorectal cancer with synchronous adenoma

Abstract

Objective

To investigate the clinicopathological and molecular features of colorectal cancer (CRC) with synchronous adenoma and to describe features of synchronous adenomas in CRC patients.     

Esophageal Squamous Cell Carcinoma Patients Have an Increased Risk of Coexisting Colorectal Neoplasms

Background/Aims

Esophageal squamous cell carcinoma (ESCC) and colorectal neoplasms (CRNs) share risk factors. We aimed to investigate whether the CRN risk is increased in ESCC patients.

Methods

ESCC patients who underwent a colonoscopy within 1 year of diagnosis were retrospectively analyzed. Patients were matched 1:3 by age, gender, and body mass index to asymptomatic controls. CRN was defined as the histological confirmation of adenoma or adenocarcinoma. Advanced CRN was defined as any of the following: ≥3 adenomas, high-grade dysplasia, villous features, tumor ≥1 cm, or adenocarcinoma. The risk factors for both CRN and advanced CRN were evaluated by univariate and multivariate analyses.

Results

Sixty ESCC patients were compared with 180 controls. The ESCC group had significantly higher numbers of CRNs (odds ratio [OR], 2.311; 95% confidence interval [CI], 1.265 to 4.220; p=0.006) and advanced CRNs (OR, 2.317; 95% CI, 1.185 to 4.530; p=0.013). Significant risk factors for both CRN and advanced CRN by multivariate analysis included ESCC (OR, 2.157, 95% CI, 1.106 to 4.070, p=0.024; and OR, 2.157, 95% CI, 1.045 to 4.454, p=0.038, respectively) and older age (OR, 1.068, 95% CI, 1.032 to 1.106, p<0.001; and OR, 1.065, 95% CI, 1.024 to 1.109, p=0.002, respectively).

Conclusions

The rates of CRN and advanced CRN are significantly increased in ESCC. Colonos-copy should be considered at ESCC diagnosis.     

Accumulation of aberrant DNA methylation during colorectal cancer development

Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.     

The expression of CD66a and possible roles in colorectal adenoma and adenocarcinoma

Background The aim of our study was to analyze the expression and possible role of CD66a in colorectal adenoma and adenocarcinoma and the relationship between its expression and pre-operation serum carcinoembryonic antigen (CEA) level and tumor stage in patients with colorectal adenocarcinomas. Methods Paraffin-embedded sections from 184 patients including 42 colorectal adenomas with low-grade dysplasia, 43 adenomas with high-grade dysplasia, and 99 adenocarcinomas were collected for this study. Immunohistochemical analysis was performed, and the expression and the location of CD66a were evaluated and were correlated with β-catenin nuclear expression. Results The expression of CD66a was found not only in the apical membrane of neoplastic glands but also in secretion within the lumen of the neoplastic glands including adenomas and adenocarcinomas. Expressions of secreted CD66a were of higher level in adenocarcinoma than in adenoma with high-grade dysplasia and adenoma with low-grade dysplasia (p < 0.0001). High expression of secreted CD66a was also associated with tumor stage, invasion, and pre-operation serum CEA level of patients with colorectal adenocarcinoma. Conclusions This study implied that CD66a can function both as an epithelial cell adhesion protein or alternatively as secreted CD66a. In addition, a high expression of CD66a was significantly correlated with tumor invasion, stage, and pre-operation serum CEA level.     

Evaluation of global DNA hypomethylation in human colon cancer tissues by immunohistochemistry and image analysis

BACKGROUND: Global hypomethylation of DNA is frequently observed in human tumours. This alteration is detected in early adenomas in colorectal tumorigenesis. Information is currently acquired after extraction of DNA from tissues, digestion with nucleases, and analysis by reverse phase chromatography, or treatment with restriction enzymes followed by gel electrophoresis analysis and Southern hybridisation with radiolabelled probes. AIMS: The purpose of our work was to evaluate the global methylation status of DNA in malignant lesions without loosing the histopathological features of the samples. PATIENTS: The investigation was performed on paired normal-tumour tissues from 13 patients undergoing surgical resection of colorectal adenocarcinomas. METHODS: Antibodies raised against 5-methylcytidine can be used to label methyl rich regions in interphase nuclei. This technique was adapted to the study of paraffin embedded tissues and an immunohistochemical method was developed to assess the global methylation status of individual nuclei while preserving cell morphology and tissue architecture. Computer assisted quantification of the staining intensity was performed on malignant and normal zones of human colon tissues to test the correlation between the immunolabelling signal and the respective histological patterns observed. RESULTS: Qualitative and quantitative differences were observed and measured between the normal and malignant part of each sample. Morphologically altered nuclei displayed densely labelled spots within faintly labelled areas whereas normal nuclei were darker and uniformly stained. Image analysis allowed calculation of the average integrated optical density of the nuclei in both types of tissues, demonstrating a constant and significantly lower intensity for the former type of cells.     

Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer

Objective. Heme oxygenase-1 (HO-1) has emerged as a crucial mediator of mucosal defense in the gastrointestinal tract. Its metabolic pathway products, biliverdin/bilirubin and carbon monoxide, can reduce oxidative stress and inflammation, and promote resistance to apoptosis. The role of HO-1 in gastrointestinal malignancies, however, remains to be elucidated. The purpose of this study was to analyze HO-1 expression in human colon adenoma and cancer samples. Material and methods. Fifty-five paraffin-embedded surgical specimens of colorectal cancer and 19 colonic adenoma samples were stained immunhistochemically for HO-1 expression using an anti-HO-1 monoclonal antibody. HO-1 expression was evaluated independently by two different investigators and subsequently correlated to clinical data and patients’ life expectancy. Results. Focal HO-1 expression could be documented in 41.8% (23/55) of patients with colorectal cancer. HO-1 expression in colonic adenoma was detectable in 36.8% (7/19) of cases. The rate of lymphatic tumor invasion was significantly lower in colorectal cancer samples expressing HO-1 (p=0.048). Additionally, fewer lymph node metastases were found in colorectal cancer samples with HO-1 expression, but these differences did not reach statistical significance. Mean observation period was 65.87±3.96 months. Kaplan-Meier analysis showed a significantly better survival for colorectal cancer patients with colonic HO-1 expression (p=0.018). Conclusions. This study demonstrates that colonic HO-1 may be a prognostic marker of colorectal-cancer outcome.     

Immunohistochemical Expression of PCNA and CD34 in Colorectal Adenomas and Carcinomas Using Specified Automated Cellular Image Analysis System: A Clinicopathologic Study

Background/Aim:

To evaluate the immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and CD34 in colorectal adenomas and carcinomas, and to correlate this expression with different clinicopathologic parameters.

Materials and Methods:

The study was retrospectively designed. A total of 86 tissue samples, including 33 paraffin blocks from patients with colorectal adenomas, 33 paraffin blocks from patients with colorectal adenocarcinomas, and a control group of 20 samples of nontumerous colonic tissue, were included in the study. From each block, 3 sections of 5 ΅m thickness were taken, 1 section was stained with hematoxylin and eosin (H and E) and the other 2 sections were stained immunohistochemically for PCNA and CD34. Scoring of the immunohistochemical staining was performed using a specified automated cellular image analysis system (Digimizer).

Results:

PCNA expression was significantly increased in a sequence of normal mucosa–adenoma–carcinoma. It was significantly higher in adenomas ≥ 1 cm and those with severe dysplasia, and it showed a significant positive correlation with grade and lymph node involvement in colorectal carcinoma. CD34 showed significantly higher expression in carcinoma than adenoma and in adenoma than in the control group. CD34 expression showed a significant correlation with adenomas carrying severe dysplasia and large-sized adenomas (≥1cm). It was significantly correlated with tumor grade, lymphovascular invasion, and lymph node involvement in colorectal carcinoma.

Conclusion:

PCNA plays an important role in colorectal neoplastic progression and can be utilized as ancillary marker for the risk of malignant transformation in colorectal adenomas as it correlates with high grade dysplasia and size. Intratumoral quantification of the mean (A and N) of CD34 in colorectal carcinoma reflects the grade of tumors and can predict lymph node involvement and lymphovascular invasion, to make a useful additional prognostic factor.     

Immunohistochemical Expression of Matrix Metalloproteinase-7 in Human Colorectal Adenomas Using Specified Automated Cellular Image Analysis System: A Clinicopathological Study

Background/Aim:

To evaluate the immunohistochemical expression of matrix metalloproteinase-7 (MMP-7) in colorectal adenomas, and to correlate this expression with different clinicopathological parameters.

Patients and Methods:

The study was retrospectively designed. Thirty three paraffin blocks from patients with colorectal adenoma and 20 samples of non-tumerous colonic tissue taken as control group were included in the study. MMP-7 expression was assessed by immunohistochemistry method. The scoring of immunohistochemical staining was conducted utilizing a specified automated cellular image analysis system (Digimizer).

Results:

The frequency of positive immunohistochemical expression of MMP-7 was significantly higher in adenoma than control group (45.45% versus 10%) (P value < 0.001). Strong MMP-7 staining was mainly seen in adenoma cases (30.30%) in comparison with control (0%) the difference is significant (P < 0.001). The three digital parameters of MMP-7 immunohistochemical expression (Area (A), Number of objects (N), and intensity (I)) were significantly higher in adenoma than control. Mean (A and I) of MMP-7 showed a significant correlation with large sized adenoma (≥ 1cm) (P < 0.05), also a significant positive correlation of the three digital parameters (A, N, and I) of MMP-7 expression with villous configuration and severe dysplasia in colorectal adenoma had been identified (P < 0.05).

Conclusion:

MMP-7 plays an important role in the growth and malignant conversion of colorectal adenomas as it is more likely to be expressed in advanced colorectal adenomatous polyps with large size, severe dysplasia and villous histology. The use of automated cellular image analysis system (Digmizer) to quantify immunohistochemical staining yields more consistent assay results, converts semi-quantitative assay to a truly quantitative assay, and improves assay objectivity and reproducibility.     

Insulin Therapy and Colorectal Adenoma Risk Among Patients with Type 2 Diabetes Mellitus: A Case-Control Study in Korea

Purpose Patients with Type 2 diabetes mellitus may be at increased colorectal adenoma and cancer risk. Moreover, chronic insulin therapy may increase the risk of colorectal cancer among patients with Type 2 diabetes mellitus. We investigated to determine whether insulin therapy might increase the risk of colorectal adenoma among clinically confirmed patients with Type 2 diabetes mellitus. Methods We conducted a retrospective study among patients with Type 2 diabetes mellitus who underwent total colonoscopy between January 2003 and July 2006 at Hallym University Sacred Heart Hospital. Among them (n = 325), patients with histologically confirmed colorectal adenomas (n = 100) and the same number of controls matched by age and sex were selected and analyzed. Results Adenoma cases showed significantly higher rate of chronic insulin therapy (more than 1 year) than controls (P = 0.018). In multivariate regression analysis, patients who received chronic insulin therapy had three times the risk of colorectal adenoma compared with patients who received no insulin (odds ratio, 3; 95 percent confidence interval, 1.1–8.9; P = 0.04). Conclusions Chronic insulin therapy was associated with increased colorectal adenoma risk among Type 2 diabetes mellitus patients. This result may provide a need for more intensive colorectal cancer screening program in patients with Type 2 diabetes mellitus, especially those who receive chronic insulin therapy.     

Diagnostic Yield in a Biennial Hemoccult-II Screening Program Compared to a Once-only Screening with Flexible Sigmoidoscopy and Hemoccult-II

Background: Flexible sigmoidoscopy (FS) has a higher degree of sensitivity for detecting colorectal neoplasia in the left side of the colon than Hemoccult-II (H-II). However, no randomized controlled trial has compared a single FS screening with H-II screening program (annual or biennial) despite with well-documented mortality reduction from colorectal cancer (CRC) in the latter. The aim was to compare the diagnostic yield of colorectal neoplasia in two aged-matched groups from two different randomized screening trials; one group screened by a single FS+H-II, the other with biennial H-II over the course of 16 years. Methods: 24,465 persons invited to participate in the Funen biennal H-II screening program were compared with 4,460 similar persons invited to another Funen trial using a single FS+H-II. Results: Compliance in the biennial H-II program was 65.5% during the first screening round compared to 39.8% for FS+H-II. The cumulative number of persons with positive tests was 8.2% (positive H-II) in the biennial H-II program during 16 years and 20.3% (polyps > 3 mm in diameter seen at FS or positive H-II) for once-only FS+H-II. The diagnostic yield of CRC per 1,000 screened was 9.9 in the biennial H-II program and 6.6 after FS+H-II (6.5 and 2.7 per 1,000 invited). The yield of advanced adenomas (≥ 10 mm and/or villous structure and/or severe dysplasia) was 2.3% in the H-II program and 3.3% after FS+H-II among the screened persons, but this difference disappeared when persons invited, but not necessarily screened, were compared (1.5% versus 1.3%). Conclusion: Screening with H-II in a biennial screening program during 16 years detected more CRCs than a single screening with FS+H-II and a similar number of advanced adenomas.     

Flow cytometry of colorectal carcinoma with three-year follow-up

Flow cytometry DNA measurements were carried out on colorectal carcinomas from a series of 33 patients who have since been followed for three to four years. The tumors could be subclassified by this technique into 15 that had near-diploid DNA and 18 that were aneuploid. Prior reports had suggested that the near-diploid tumors carry a better prognosis than aneuploid tumors, but in this study the distribution by Dukes' stage and survival were the same in both groups. supported by NCI Grants No. CA-34134 and CA-31545.     

Clinical features and molecular alterations of traditional serrated adenoma in sporadic colorectal carcinogenesis

OBJECTIVE: To compare clinical features and molecular alterations between traditional serrated adenomas (TSA) & serrated carcinomas (SCa) and traditional adenomas (TA) & carcinomas (Ca) of the colorectum and to verify a traditional serrated pathway of sporadic colorectal carcinogenesis. METHODS: One thousand two hundred slides of colorectal polyps obtained from 1160 patients were collected and reviewed to define TSA and clinical and pathological features were analyzed and compared with TA. DNA was extracted from specimens of TSA, TA, SCa and Ca, v‐raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutation and microsatellite instability (MSI) (assay for BAT25 and BAT26) were analyzed. RESULTS: Overall 29 TSA were confirmed (2.5%), and there was an age difference between patients with TSA and TA (56.0 vs 62.7, P < 0.05). Compared with TA, TSA was located more often in the rectosigmoid colon (TSA 62.1% vs TA 35.2%, P < 0.05), but occurred less in the descending colon (TSA 0% vs TA 25.35%, P = 0.0068). No difference was found in terms of gender and the size or pedicles of polyps (P > 0.05). The BRAF V600E mutation was detected in 36.3% of SCa and 26.7% of TSA patients, but it was not detected in TA and Ca patients; MSI‐H was noticed in 23% of SCa, 33.3% of TSA, 5.3% of Ca and 0% of TA patients, respectively (P < 0.05). CONCLUSION: There might be a traditional serrated pathway of sporadic colorectal carcinogenesis that is different from the conventional adenoma to carcinoma carcinogenesis pathway in the colorectum.